Implantable medical device and method for in situ selective modulation of agent delivery

ABSTRACT

The present invention provides an implantable medical device, systems employing the device, and methods of using the device. The implantable medical device includes a device body containing a beneficial agent arranged for delivery from the device body to an implantation site within a patient. The beneficial agent is configured to be selectively modulated after implantation within the patient by an activating/deactivating means. Furthermore, the beneficial agent at a first region of the device body can be modulated by the activating/deactivating means to create a different agent delivery profile than the beneficial agent at a second region of the device body.

CROSS REFERENCE PATENT INFORMATION

[0001] This application claims priority under 35 U.S.C. § 119 to U.S.Provisional Application No. 60/458,906 entitled Implantable MedicalDevice and Method for In Situ Selective Modulation of Agent Deivery andfiled on Mar. 23, 2003.

FIELD OF THE INVENTION

[0002] The invention relates to an implantable medical device and methodfor delivery of an agent to a location within a patient, and moreparticularly, the invention relates to the selective modulation of agentdelivery from the implantable medical device.

DESCRIPTION OF THE RELATED ART

[0003] Implantable medical devices are often used for delivery of abeneficial agent, such as a drug, to an organ or tissue in the body at acontrolled delivery rate over an extended period of time. These devicesmay deliver agents to a wide variety of bodily systems to provide a widevariety of treatments.

[0004] One of the many implantable medical devices which have been usedfor local delivery of beneficial agents is the vascular stent. Vascularstents are typically introduced percutaneously, and transportedtransluminally until positioned at a desired location. These devices arethen expanded either mechanically, such as by the expansion of a mandrelor balloon positioned inside the device, or expand themselves byreleasing stored energy upon actuation within the body. Once expandedwithin the lumen, these devices, called stents, become encapsulatedwithin the body tissue and remain a permanent implant.

[0005] Known stent designs include monofilament wire coil stents (U.S.Pat. No. 4,969,458); welded metal cages (U.S. Pat. Nos. 4,733,665 and4,776,337); and, most prominently, thin-walled metal cylinders withaxial slots formed around the circumference (U.S. Pat. Nos. 4,733,665;4,739,762; and 4,776,337). Known construction materials for use instents include polymers, organic fabrics and biocompatible metals, suchas stainless steel, gold, silver, tantalum, titanium, cobalt basedalloys, and shape memory alloys, such as Nitinol.

[0006] Of the many problems that may be addressed through stent-basedlocal delivery of beneficial agents, one of the most important isrestenosis. Restenosis is a major complication that can arise followingvascular interventions such as angioplasty and the implantation ofstents. Simply defined, restenosis is a wound healing process thatreduces the vessel lumen diameter by extracellular matrix deposition,neointimal hyperplasia, and vascular smooth muscle cell proliferation,and which may ultimately result in renarrowing or even reocclusion ofthe lumen. Despite the introduction of improved surgical techniques,devices, and pharmaceutical agents, the overall restenosis rate is stillreported in the range of 25% to 50% within six to twelve months after anangioplasty procedure. To treat this condition, additionalrevascularization procedures are frequently required, thereby increasingtrauma and risk to the patient.

[0007] One of the techniques under development to address the problem ofrestenosis is the use of various beneficial agents in or on stents. U.S.Pat. No. 5,716,981, for example, discloses a stent that issurface-coated with a composition comprising a polymer carrier andpaclitaxel (a well-known compound that is commonly used in the treatmentof cancerous tumors). The patent offers detailed descriptions of methodsfor coating stent surfaces, such as spraying and dipping, as well as thedesired character of the coating itself: it should “coat the stentsmoothly and evenly” and “provide a uniform, predictable, prolongedrelease of the anti-angiogenic factor.” Surface coatings, however, canprovide little actual control over the release kinetics of beneficialagents. These coatings are necessarily very thin, typically 5 to 8microns deep. The surface area of the stent, by comparison is verylarge, so that the entire volume of the beneficial agent has a veryshort diffusion path to discharge into the surrounding tissue.

[0008] Increasing the thickness of the surface coating has thebeneficial effects of improving drug release kinetics including theability to control drug release and to allow increased drug loading.However, the increased coating thickness results in increased overallthickness of the stent wall. This is undesirable for a number ofreasons, including increased trauma to the vessel wall duringimplantation, reduced flow cross-section of the lumen afterimplantation, and increased vulnerability of the coating to mechanicalfailure or damage during expansion and implantation. Coating thicknessis one of several factors that affect the release kinetics of thebeneficial agent, and limitations on thickness thereby limit the rangeof release rates, duration of drug delivery, and the like that can beachieved.

[0009] In addition to sub-optimal release profiles, there are furtherproblems with surface coated stents. The fixed matrix polymer carriersfrequently used in the device coatings typically retain approximately30%-80% of the beneficial agent in the coating indefinitely. Since thesebeneficial agents are frequently highly cytotoxic, sub-acute and chronicproblems such as chronic inflammation, late thrombosis, and late orincomplete healing of the vessel wall may occur. Additionally, thecarrier polymers themselves are often highly inflammatory to the tissueof the vessel wall. On the other hand, use of biodegradable polymercarriers on stent surfaces can result in the creation of “virtualspaces” or voids between the stent and tissue of the vessel wall afterthe polymer carrier has degraded, which permits differential motionbetween the stent and adjacent tissue. Resulting problems includemicro-abrasion and inflammation, stent drift, and failure tore-endothelialize the vessel wall.

[0010] One drawback of known stents with drugs in or on the stents isthe inability to tailor drug delivery to the tissue structure presentadjacent the implanted device. The drug delivered from a drug deliverystent is delivered to all the tissue supported by the stent includingboth the diseased tissue (lesion) and neighboring relatively healthytissue. The delivery of an anti-restenosis drug or other drugs torelatively healthy tissue in addition to the tissue to be treated may insome cases cause damage to this relatively healthy tissue. For example,aneurysms have been observed to form in the wall of a blood vessel in aportion of the blood vessel which is supported by the stent and has noapparent lesions, i.e. the relatively healthy tissue close to thediseased tissue, while similar anueysms have not been observed in thediseased tissue. However, due to a combination of stent placementinaccuracies and a requirement to support the entire diseased tissuesite, a stent must support both the diseased tissue and some relativelyhealthy tissue. It may also be desirable to deliver variable amounts ofthe drug to different tissue for many other reasons.

[0011] Accordingly, it would be desirable to provide an implantablemedical device for delivery of agents, such as drugs, to a patient andselectively modulating, activating, or deactivating agent delivery afterimplantation to provide agents at targeted tissue areas adjacent theexpandable medical device.

SUMMARY OF THE INVENTION

[0012] The present invention provides an implantable medical device,systems employing the device, and methods of using the device.

[0013] In a device aspect, the present invention provides an implantablemedical device that includes a device body containing a beneficial agentarranged for delivery from the device body to an implantation sitewithin a patient. The beneficial agent is configured to be selectivelymodulated after implantation within the patient by anactivating/deactivating means. Furthermore, the beneficial agent at afirst region of the device body can be modulated by theactivating/deactivating means to create a different agent deliveryprofile than the beneficial agent at a second region of the device body.

[0014] In a beneficial agent delivery system aspect, the presentinvention provides an implantable medical device and a selectivemodulation catheter. The implantable medical device includes abeneficial agent arranged for delivery to an implantation site within apatient, where the beneficial agent is configured to be modulated afterimplantation within the patient by an activating/deactivating means. Theselective modulation catheter has an activating/deactivating meansconfigured to activate or deactivate the beneficial agent on a firstregion of the medical device to create a different delivery profile thanthe beneficial agent on a second region of the medical device.

[0015] In another beneficial agent delivery system aspect, the presentinvention provides an expandable implantable stent, a beneficial agentaffixed to the stent, and an activating/deactivating means. Thebeneficial agent has an initial agent release profile, which can bemodulated by the activating/deactivating means after implantation of thestent within a patient. This creates an agent release profile differentfrom the initial agent release profile.

[0016] In a method aspect, the present invention provides a method ofbeneficial agent delivery with selective modulation of beneficial agentdelivery. The method involves at least the following steps: 1)implanting an implantable medical device within a patient, where thedevice includes a beneficial agent; 2) delivering an activation means toa location of the implanted medical device; and, 3) modulating theamount of drug delivered from a first region of the implanted medicaldevice with the activation/deactivation means without modulating theamount of beneficial agent delivered from a second region of theimplanted medical device.

[0017] In another method aspect, the present invention provides a methodof beneficial agent delivery from a stent. The method involves at leastthe following steps: 1) implanting a stent that includes a firstbeneficial agent and a second benefical agent within a lumen; 2)delivering the first beneficial agent from the stent; 3) determiningwhether the second beneficial agent is to be delivered; 4) delivering anactivation means to the stent; and, 5) modulating the amount of secondbeneficial agent delivered from the stent with the activation means.

[0018] In a further method aspect, the present invention provides amethod of beneficial agent delivery from a stent. The method involves atleast the following steps: 1) implanting a stent that includes a firstbeneficial agent; 2) delivering the first beneficial gent from thestent; 3) determining when delivery of the first beneficial agent is tobe terminated; 4) delivering a deactivation means to the stent; and, 5)substantially terminating the amount of second beneficial agentdelivered from the stent with the deactivation means.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0019] The invention will now be described in greater detail withreference to the preferred embodiments illustrated in the accompanyingdrawings, in which like elements bear like reference numerals, andwherein:

[0020]FIG. 1 is a side cross sectional view of an implantable beneficialagent delivery device and activation/deactivation means according to oneexample of the invention.

DETAILED DESCRIPTION OF THE INVENTION

[0021] The device of the invention comprises a stent and a drug deliverymaterial therein or thereon such that the amount of drug delivered fromone region of the stent can be modulated relative to the amountdelivered from another region of the stent, such differential modulationbeing specified after the deployment of the stent into a mammal.

[0022]FIG. 1 illustrates an implantable medical device 10 implantedwithin a blood vessel 100. As shown in FIG. 1, the blood vessel 100includes a lesion 110 which has been expanded by expansion of themedical device 10. In addition to supporting the lesion 110 or otherunhealthy tissue, the expanded medical device 10 also supports one ormore regions of relatively healthy blood vessel tissue 120. In theillustrated example, the relatively healthy tissue 120 is adjacent anend region of the medical device 10.

[0023] The expandable medical device 10 includes a plurality of openings20 containing a beneficial agent to be delivered to the tissue. Some ofthe openings 20 are adjacent the lesion 110 and some of the openings areadjacent to the relatively healthy tissue 120. The present inventionprovides an activating/deactivating device in the form of a catheter 200which is configured to be delivered over a guidewire 300 into the lumenof the medical device 10 after implantation to activate and/ordeactivate the beneficial agent(s) within the openings 20 to providetargeted modulation of delivery of the beneficial agent to deliver thebeneficial agent to specific regions or locations from a surface of theimplanted medical device 10.

[0024] In the case of a beneficial agent which is useful for reducingextracellular matrix deposition, neointimal hyperplasia, and vascularsmooth muscle cell proliferation, which may ultimately result inrenarrowing or even reocclusion of the lumen the beneficial agent can beactivated adjacent the lesion 110 or deactivated adjacent to relativelyhealthy tissue 120 to deliver the majority of the beneficial agent,preferably a therapeutically effective amount of the beneficial agent,to the targeted tissue.

[0025] The term “modulation” refers to the adjustment of the amount ofbeneficial agent delivered or the beneficial agent delivery rate eitherby activating or deactivating. Modulation of the amount of drugdelivered is envisioned to include the range from no delivery of drugcontained in a specified region, to delivery of a portion of the drugfrom a region, to delivery of the entire drug contained in a specifiedregion of the stent.

[0026] The terms “activating and deactivating” refer to the activationor release of a beneficial agent or the deactivation, blocking, orremoval of a beneficial agent. It may include altering the properties ofthe beneficial agent to render it active or inactive. It may alsoinclude altering materials surrounding the beneficial agent to increaserelease or decrease or prevent release of the beneficial agent. It mayfurther include degrading or removing a compound in a barrier or matrixlayer to allow delivery of a beneficial agent or to allow removal of abeneficial agent, such as by flushing the agent away in the bloodstream. Activation generally results in delivery of a therapeutic agentof a therapeutically effective amount at a therapeutically effectiverelease rate. Deactivation generally results in delivery of atherapeutically ineffective amount or delivery at a therapeuticallyineffective release rate. Activation generally results in increasedrates of delivery of an agent to target tissue as compared to thedelivery rate prior to activation, while deactivation generally resultsin decreased rates of delivery of an agent to the target tissue ascompared to the delivery rate prior to deactivation.

[0027] The term “beneficial agent” as used herein is intended to havethe broadest possible interpretation and is used to include anytherapeutic agent or drug, as well as inactive agents such as barrierlayers, carrier layers, therapeutic layers or protective layers. Thebeneficial agent may be comprised of a drug alone, or may additionallycontain nondrug material to act as a matrix or binder to hold the drugcontaining material within or on the stent and/or modulate the releaseof the drug from a region of the stent.

[0028] The terms “drug” and “therapeutic agent” are used interchangeablyto refer to any therapeutically active substance that is delivered totissue of a living being to produce a desired, usually beneficial,effect. The present invention is particularly well suited for thedelivery of antineoplastic, angiogenic factors, immuno-suppressants, andantiproliferatives (anti-restenosis agents) such as paclitaxel andRapamycin for example, and antithrombins.

[0029] The term “matrix” or “biocompatible matrix” are usedinterchangeably to refer to a medium or material that, upon implantationin a subject, does not elicit a detrimental response sufficient toresult in the rejection of the matrix. The matrix typically does notprovide any therapeutic responses itself, though the matrix may containor surround a therapeutic agent, a therapeutic agent, an activatingagent or a deactivating agent, as defined herein. A matrix is also amedium that may simply provide support, structural integrity orstructural barriers. The matrix may be polymeric, non-polymeric,hydrophobic, hydrophilic, lipophilic, amphiphilic, and the like.

[0030] The term “bioerodible” refers to a matrix, as defined herein,that is bioresorbable and/or can be broken down by either chemical orphysical process, upon interaction with a physiological environment. Thebioerodible matrix is broken into components that are metabolizable orexcretable, over a period of time from minutes to years, preferably lessthan one year, while maintaining any requisite structural integrity inthat same time period.

[0031] Although the invention is described herein with reference to theexample of a stent containing a beneficial agent within holes fordelivery of the beneficial agent to the walls of a lumen, it should beunderstood that other devices may be used and the devices may be used totreat other tissue structures. For example, the drug delivery device canbe an expandable vascular stent, urethral stent, biliary stent, shunt,or another implantable device. The beneficial agent from the implantablemedical device can be differentially delivered to any two differenttypes of tissues or tissue structures, for example, different tissue ortissue structures may include plaques of different types, healthytissue, cancerous tissues, injured tissue, and tissue adjacent variousstructures, such as bifurcations.

[0032] The term “polymer” refers to molecules formed from the chemicalunion of two or more repeating units, called monomers. Accordingly,included within the term “polymer” may be, for example, dimers, trimersand oligomers. The polymer may be synthetic, naturally-occurring orsemisynthetic. In preferred form, the term “polymer” refers to moleculeswhich typically have a M_(w) greater than about 3000 and preferablygreater than about 10,000 and a M_(w) that is less than about 10million, preferably less than about a million and more preferably lessthan about 200,000. Examples of polymers include but are not limited to,poly-α-hydroxy acid esters such as, polylactic acid (PLLA or DLPLA),polyglycolic acid, polylactic-co-glycolic acid (PLGA), polylacticacid-co-caprolactone; poly (block-ethyleneoxide-block-lactide-co-glycolide) polymers (PEO-block-PLGA andPEO-block-PLGA-block-PEO); polyethylene glycol and polyethylene oxide,poly (block-ethylene oxide-block-propylene oxide-block-ethylene oxide);polyvinyl pyrrolidone; polyorthoesters; polysaccharides andpolysaccharide derivatives such as polyhyaluronic acid, poly (glucose),polyalginic acid, chitin, chitosan, chitosan derivatives, cellulose,methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose,carboxymethylcellulose, cyclodextrins and substituted cyclodextrins,such as beta-cyclodextrin sulfobutyl ethers; polypeptides and proteins,such as polylysine, polyglutamic acid, albumin; polyanhydrides;polyhydroxy alkonoates such as polyhydroxy valerate, polyhydroxybutyrate, and the like.

[0033] It is envisioned that the pattern of regions on the stent createdwhich deliver differing amounts of the drug contained in each region bespecified based on the physiology and pathology of a region of a lumenor other tissue being treated by the medical device and drug ortherapeutic agent. Further, the regions are envisioned to include bothregions on the mural side of the stent and on the luminal side of thestent.

[0034] It is envisioned in one embodiment that the stent will includebeneficial agent that is initially disposed in a spatially uniformmanner in the stent and later specific areas of the stent are treateddifferentially by an activating/deactivating means to create aregio-specific pattern of amount of agent to be delivered afterdeployment of the stent. Additionally, the beneficial agent mayinitially contain a pro-drug or a blocked drug which by later treatmentis converted from a therapeutically inactive form into the active drugfor delivery from that specific area. This process is generally calledactivation of a drug.

[0035] Conversely, starting with a stent with a uniform distribution ofbeneficial agent therein, it is envisioned to create an inhomogeneouspattern of regions that will release active drug and regions that willnot release or will only release a limited amount of active drug byselectively degrading or otherwise rendering the drug contained inspecific regions of the stent therapeutically inactive. This process isgenerally called deactivation of a drug.

[0036] Further, it is envisioned to render the drug containing materialin a specific region more able or less able to release the drugcontained in that region by selectively treating and effecting amodification the non-drug component of the drug delivery material toprovide a modulation of drug release amount. This process is generallycalled activation or deactivation by modification of the matrix.

[0037] It is also envisioned to render the beneficial agent in aspecific region more or less able to be released in that region byselectively treating and modifying a structure other than the beneficialagent. For example, a barrier layer may be made more or less permeableto the drug to allow the drug to be delivered, to substantially preventdrug delivery, or to allow the drug to be delivered and washed away bythe blood stream or other means.

[0038] Various activation/deactivation means including energy andchemicals are envisioned to effect the modulation of drug deliverycapability of specific drug containing regions on the stent bymodification variously of the drug or a pro-drug, or of the matrix orbinder component of the drug delivery material, or of another structure,such as a barrier layer.

[0039] In the embodiment illustrated in FIG. 1, the openings 20 in thestent 10 allow easy accessability for the activating/deactivating meansin the form of either energy or chemicals to be delivered to thebeneficial agent. Without the openings, it may be difficult for sometypes of energy, including light, and chemicals to be delivered from anactivation/deactivation means within the lumen of the stent to a muralside of the stent to perform the activation or deactivation.

[0040] It is envisioned that a drug in a specific region of the medicaldevice that is not in an active form in the initial beneficial agent maybe activated by treating the drug to change the ambient pH value, or bydegrading an antagonist to the drug, or by adding an activatingco-factor such as a metal salt or an enzyme that will convert the drugto an active form. The drug may initially be present in a blocked formand may be activated by treatment with a de-blocking agent such as anacid, base, or salt. The drug may initially be present in the beneficialagent as a pro-drug where the drug is bound to another moiety or polymervia a labile linkage, in which case it cannot be released as an activedrug, but by treatment variously with an enzymatic agent, such as if thelabile linkage contains peptide bonds, or by treatment with actinicradiation, such as light, if the linkage is a photo-labile linkage sucha alpha, beta dicarbonyl or alpha hydroxyl or alkoxyl carbonyl linkage.

[0041] Conversely, it is envisioned that in a system where thebeneficial agent is initially present so that the distribution of drugis uniform along the stent, a pattern of drug releasing and non-drugreleasing regions may be created by degrading or otherwise rendering thedrug in some regions therapeutically inactive by local treatment ofspecific regions on the stent. A chemical agent may be added to bind tothe drug to inactivate it, or an oxidant or reductant added tochemically modify the therapeutic agent. The species effecting thechemical de-activation of the drug in a local region may be generated insitu, such as by the action of actinic radiation to create oxidizingspecies.

[0042] Additionally, it is envisioned that the treatment of local areaswith light alone, especially light of a wavelength that matches thewavelength of maximum light absorbance of the drug, can effect thede-activation of the drug variously by the processes of rearrangement,scission, or change from an active to an inactive conformation. Further,a chemical agent or application of an energy source, such as light, todegrade a stabilizer for the drug contained in the drug deliverymaterial is envisioned as a method to decrease or eliminate the abilityto deliver active drug from that region.

[0043] Various treatments applied to the matrix or binder component ofthe drug delivery material are envisioned as methods to locally controlthe delivery of drug from a region of the stent. In one embodiment,treatment of a polymer matrix that contains reactive groups capable ofcross-linking the matrix and holding the drug more tenaciously with across-linking reagent or energy is envisioned as a method to decreasethe amount of drug that can be delivered from a region so treated.Conversely, a polymer matrix containing linkages that are chemically orphoto-chemically labile can result in a matrix that is unable to holddrug effectively and drug in these regions will be released prematurelyand create regions depleted of drug in the area for therapeutictreatment.

[0044] Further, it is envisioned to initially confine the drug in aconstruct, such as a liposome, solid lipid nano-particle, micelle, solidemulsion, cage clathrate complex, or micro-particle within the drugdelivery material, either alone or within the matrix or bindercomponent. Specific local regions containing such drug containingconstructs in the stent can be treated with local energy to rupture theconstruct and release the drug pre-maturely, such as into the lumen of avessel. Such drug will be lost and render such a region devoid of drugfor the purposes of therapeutic activity and can be considered a form ofdeactivation. Conversely, the drug may be encapsulated within aconstruct that does not allow drug or therapeutic agent to be releasedwithin the time period of therapeutic treatment, such as in the case ofa hydrophobic drug encased or sequestered in the core of a hydrophilicshell material. Without treatment to release the drug from theconstruct, little or no drug will be released from that region of thestent. However, the drug may be selectively transferred from theconstruct into the drug delivery material, where it will then beavailable for future delivery to tissue, by local application of energyto specific regions of the stent to rupture the shell of the constructand allow the drug to enter the drug delivery material in a form thatcan further be released from the stent. The energy to cause the releaseof drug from the construct into the drug delivery matrix, such as by therupture of the confining outer shell or membrane of the construct, isenvisioned to preferably be ultrasonic or thermal energy, such asthermal energy in the form of radio-frequency (RF) energy or fromresistive electrical heating. More preferably the energy is ultrasonic(US) energy. Further, it is envisioned that the drug is encased in thecore of a dual shell construct such that the spacing between the shelllayers causes the dual shell construct to rupture at specific resonancefrequencies of applied ultrasonic energy.

[0045] It is envisioned that the drug delivery material may be disposedon the surfaces of the stent in various configurations, including withinvolumes defined by the stent, such as holes or concave surfaces, as areservoir of drug, as a coating on all or a portion of surfaces of thestent structure, within the device material itself, as a sleeve ofmaterial positioned over the device, as agent threads woven through thedevice, or in any other configuration.

[0046] When the drug delivery material is disposed within holes in thestrut structure of the stent to form a reservoir, the holes may bepartially or completely filled with material. Additionally, thecomposition of the drug delivery material within the holes may becomprised of a plurality of individual layers, each with the same ordifferent compositions with respect to the amount of drug and the amountof matrix or binding material comprising the drug delivery material. Itis further envisioned that in the above described activation ordeactivation of material located at specific sites or regions of thestent, drug containing material may comprise one drug in one region ofthe stent and another drug in a region distinct from the first region,such that two or more drugs may be independently treated to provideindependent region specific patterns for simultaneous or sequentialdelivery of two or more drugs or therapeutic agents. More than onebeneficial agent can be provided in alternating or interspersed holesfor a uniform initial arrangement of more than one beneficial agentacross the stent surface, wherein one agent is delivered withoutactivation and one agent requires activation. Alternately, more than onebeneficial agent may be activated or deactivated simultaneously orsequentially by the same or different activation/deactivation means.

[0047] Barrier layers can also be formulated to be activated by an agentwhich could change the porosity of the barrier layer and/or change therate of bio-degradation of the barrier layer or the bulk beneficialagent carrier. In each case, release of the beneficial agent could beactivated by the physician at will by delivery of the agent.

[0048] Further, devices capable of effecting the above describedregion-specific drug activating or deactivating treatment afterdeployment of the stent are envisioned. Such activating/deactivatingdevices may be positioned either inside or outside the body. Accordingto one example, the device is a catheter-based device capable ofpercutaneous transluminal placement to position anactivating/deactivating portion of the catheter within the lumen of thestent such that activating or deactivating treatment of the beneficialagent occurs from the luminal surface of the stent by operation of adistal area of the activating/deactivating device.

[0049] The catheter-based treatment device is preferably translated tothe deployed drug delivery stent in the same manner as the balloontipped catheter used to deploy the drug delivery stent. It is envisionedthat the design of the device to effect activation or deactivation ofthe drug in the beneficial agent will be governed by the nature of thetreatment. For the delivery of actinic radiation, such as visible orultraviolet light, including laser light, the delivery device willinclude a fiber optic fiber or fiber bundle to transmit the radiantenergy to the region of the stent to be treated, as well as an opticaldevice at the distal end of the fiber to steer the light beam to thedesired treatment location. A similar device including electricallytransmissive wires connecting to a resistive element at the distal endof a device, as shown in FIG. 1, is envisioned to deliver thermal orradio frequency energy.

[0050] Another catheter based treatment device includes an intravenousultrasound (IVUS) catheter which uses ultrasound to map the tissue. TheIVUS catheter can include both the visualization means and theactivation/deactivation means. For example, the IVUS catheter mayinclude a first frequency of ultrasound energy for ultrasonic mappingand a second frequency of ultrasonic energy for activation/deactivationof drug delivery. The IVUS catheter may also be used in combination withany of the other activation/deactivation means described herein, eitherin the same or a different catheter.

[0051] One example of an activation/deactivation catheter using achemical or biological activation/deactivation means includes ballooncatheter which is impregnated or coated with the activation/deactivationagent. The activation/deactivation agent can be released from theballoon by the selective application of energy from the interior of theinflated balloon in one of the manners described above. In operation,the activation/deactivation balloon catheter is inserted into the stentand inflated so that the chemical agent, in a therapeutically inactiveform, is present on the balloon directly adjacent the interior surfaceof the stent. The chemical agent can be chemically inactive orsequestered by a matrix, barrier, or other material until released. Thechemical agent is then activated in selected region(s), such as byapplication of ultrasonic or other energy from a controllable energysource within the balloon. The chemical agent released from the balloonacts on the beneficial agent, drug, barrier layer, matrix, or binder toactivate/deactivate drug delivery in any one of the manners describedabove.

[0052] Alternatively, a balloon whose surface has been imprinted with aplurality of discreet resistive electrical circuits at locations on itssurface is envisioned to provide a method to individually treat localregions with thermal energy. The use of a balloon catheter basedactivation/deactivation means has the additional advantage ofeliminating blood from the site during activation/deactivation which canimprove visibility and accuracy.

[0053] For the delivery of chemical agents to activate or deactivatedrug in drug containing layers, a catheter with a porous balloon on itsdistal end where the individual pores or areas of pores of the balloonare connected to individual tubes whose delivery of agent can becontrolled is envisioned. Additionally, a balloon is envisioned whosesurface is porous is some areas and non-porous in others in a pattern tomatch the desired pattern of drug activation and deactivation on thestent.

[0054] The methods of the present invention generally include implantingan implantable medical device having a beneficial agent with knownprocedures. For example, a stent may be placed and expanded with aballoon catheter which is delivered transluminaly over a guidewire underfluoroscopic visualization. Upon implantation of the medical device, anactivation/deactivation means is used to selectively activate/deactivatedrug delivery in selected regions of the implanted device. For example,an activation/deactivation device on the end of a catheter can beinserted over the guidewire to the location of an implanted stent andthe beneficial agent of the stent can be activated/deactivated inregions by the surgeon by “painting” with the catheter by delivery ofenergy or chemicals under fluoroscopic visualization.

[0055] Alternatively, the step of activating/deactivating may beperformed by a activating/deactivating catheter which is maintainedfixed and is activated in specific regions from an exterior of the body.For example, a balloon catheter including a plurality of individualactivatable electric circuits, fiber optics, or chemical delivery portscan deliver the activating/deactivating energy or chemical according toa pattern selected by a surgeon by drawing on a computer image of thetissue surrounding the implant.

[0056] As described herein, the beneficial agent is preferably providedin the implantable medical device in reservoirs in a solid or nonflowable form, such as in a polymer matrix or gel. Theactivation/deactivation means is capable of activating or deactivatingthe agent in the reservoirs without the need for circuitry or powersources in the implantable device.

[0057] In another embodiment, the agent delivery from substantially theentire stent or other device may be activated or deactivated afterimplantation to begin or terminate a treatment determined to benecessary after implantation. For example, a stent containing ananti-restenotic agent and a second agent, such as an angiogenic agent,may be delivered with the stent initially releasing primarily theanti-restenotic agent. At a later date, the delivery of the second agentcan be initiated by an activating means when it is determined that thecondition of the patient requires the second agent. For example, theangiogenic agent may be released upon a determination that the hearttissue has reached an undesirable level of ischemia at which a secondagent would be beneficial. The second agent may treat a variety ofconditions, for example, the second agent may include a vasodilator, anangiogenic agent or combination of angiogenic agents, insulin, or thelike. The activation can be achieved by any of the means describedabove. In addition, chemical activation by a systemically applied agentmay be used to activate a second drug on substantially the entire stent.

[0058] In example embodiment, the agent delivered from substantially theentire stent or other device can be deactivated upon determination bythe physician that the patient's condition no longer requires thedelivery of the drug. This deactivation can be done in any of themanners described above or by systemic administration of a chemicaldeactivation means.

[0059] Therapeutic agents for use with the present invention may, forexample, take the form of small molecules, peptides, lipoproteins,polypeptides, polynucleotides encoding polypeptides, lipids,protein-drugs, protein conjugate drugs, enzymes, oligonucleotides andtheir derivatives, ribozymes, other genetic material, cells, antisenseoligonucleotides, monoclonal antibodies, platelets, prions, viruses,bacteria, eukaryotic cells such as endothelial cells, stem cells, ACEinhibitors, monocyte/macrophages and vascular smooth muscle cells. Suchagents can be used alone or in various combinations with one another.For instance, antiinflammatories may be used in combination withantiproliferatives to mitigate the reaction of tissue to theantiproliferative. The therapeutic agent may also be a pro-drug, whichmetabolizes into the desired drug when administered to a host. Inaddition, therapeutic agents may be pre-formulated as microcapsules,microspheres, microbubbles, liposomes, niosomes, emulsions, dispersionsor the like before they are incorporated into the matrix. Therapeuticagents may also be radioactive isotopes or agents activated by someother form of energy such as light or ultrasonic energy, or by othercirculating molecules that can be systemically administered.

[0060] Exemplary classes of therapeutic agents includeantiproliferatives, antithrombins (i.e., thrombolytics),immunosuppressants, antilipid agents, anti-inflammatory agents,antineoplastics including antimetabolites, antiplatelets, angiogenicagents, anti-angiogenic agents, vitamins, antimitotics,metalloproteinase inhibitors, NO donors, nitric oxide releasestimulators, anti-sclerosing agents, vasoactive agents, endothelialgrowth factors, beta blockers, hormones, statins, insulin growthfactors, antioxidants, membrane stabilizing agents, calcium antagonists(i.e., calcium channel antagonists), retinoids, anti-macrophagesubstances, antilymphocytes, cyclooxygenase inhibitors, immunomodulatoryagents, angiotensin converting enzyme (ACE) inhibitors, anti-leukocytes,high-density lipoproteins (HDL) and derivatives, cell sensitizers toinsulin, prostaglandins and derivatives, anti-TNF compounds,hypertension drugs, protein kinases, antisense oligonucleotides, cardioprotectants, petidose inhibitors (increase blycolitic metabolism),endothelin receptor agonists, interleukin-6 antagonists,anti-restenotics, and other miscellaneous compounds.

[0061] Antiproliferatives include, without limitation, sirolimus,paclitaxel, actinomycin D, rapamycin, and cyclosporin.

[0062] Antithrombins include, without limitation, heparin, plasminogen,α₂-antiplasmin, streptokinase, bivalirudin, and tissue plasminogenactivator (t-PA).

[0063] Immunosuppressants include, without limitation, cyclosporine,rapamycin and tacrolimus (FK-506), sirolumus, everolimus, etoposide, andmitoxantrone.

[0064] Antilipid agents include, without limitation, HMG CoA reductaseinhibitors, nicotinic acid, probucol, and fibric acid derivatives (e.g.,clofibrate, gemfibrozil, gemfibrozil, fenofibrate, ciprofibrate, andbezafibrate).

[0065] Anti-inflammatory agents include, without limitation, salicylicacid derivatives (e.g., aspirin, insulin, sodium salicylate, cholinemagnesium trisalicylate, salsalate, dflunisal, salicylsalicylic acid,sulfasalazine, and olsalazine), para-amino phenol derivatives (e.g.,acetaminophen), indole and indene acetic acids (e.g., indomethacin,sulindac, and etodolac), heteroaryl acetic acids (e.g., tolmetin,diclofenac, and ketorolac), arylpropionic acids (e.g., ibuprofen,naproxen, flurbiprofen, ketoprofen, fenoprofen, and oxaprozin),anthranilic acids (e.g., mefenamic acid and meclofenamic acid), enolicacids (e.g., piroxicam, tenoxicam, phenylbutazone andoxyphenthatrazone), alkanones (e.g., nabumetone), glucocorticoids (e.g.,dexamethaxone, prednisolone, and triamcinolone), pirfenidone, andtranilast.

[0066] Antineoplastics include, without limitation, nitrogen mustards(e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan, andchlorambucil), methyInitrosoureas (e.g., streptozocin),2-chloroethyInitrosoureas (e.g., carmustine, lomustine, semustine, andchlorozotocin), alkanesulfonic acids (e.g., busulfan), ethylenimines andmethylmelamines (e.g., triethylenemelamine, thiotepa and altretamine),triazines (e.g., dacarbazine), folic acid analogs (e.g., methotrexate),pyrimidine analogs (5-fluorouracil, 5-fluorodeoxyuridine,5-fluorodeoxyuridine monophosphate, cytosine arabinoside, 5-azacytidine,and 2′,2′-difluorodeoxycytidine), purine analogs (e.g., mercaptfor usewith the present invention may, for example, take the form of smallmolecules, peptides, lipoproteins, polypeptides, polynucleotidesencoding polypeptides, lipids, protein-drugs, protein conjugate drugs,enzymes, oligonucleotides and their derivatirubicin, idarubicin,epirubicin, mitoxantrone, bleomycins, plicamycin and mitomycin),phenoxodiol, etoposide, and platinum coordination complexes (e.g.,cisplatin and carboplatin).

[0067] Antiplatelets include, without limitation, insulin, dipyridamole,tirofiban, eptifibatide, abciximab, and ticlopidine.

[0068] Angiogenic agents include, without limitation, phospholipids,ceramides, cerebrosides, neutral lipids, triglycerides, diglycerides,monoglycerides lecithin, sphingosides, angiotensin fragments, nicotine,pyruvate thiolesters, glycerol-pyruvate esters, dihydoxyacetone-pyruvateesters and monobutyrin.

[0069] Anti-angiogenic agents include, without limitation, endostatin,angiostatin, fumagillin and ovalicin.

[0070] Vitamins include, without limitation, water-soluble vitamins(e.g., thiamin, nicotinic acid, pyridoxine, and ascorbic acid) andfat-soluble vitamins (e.g., retinal, retinoic acid, retinaldehyde,phytonadione, menaqinone, menadione, and alpha tocopherol).

[0071] Antimitotics include, without limitation, vinblastine,vincristine, vindesine, vinorelbine, paclitaxel, docetaxel,epipodophyllotoxins, dactinomycin, daunorubicin, doxorubicin,idarubicin, epirubicin, mitoxantrone, bleomycins, plicamycin andmitomycin.

[0072] Metalloproteinase inhibitors include, without limitation, TIMP-1,TIMP-2, TIMP-3, and SmaPI.

[0073] NO donors include, without limitation, L-arginine, amyl nitrite,glyceryl trinitrate, sodium nitroprusside, molsidomine,diazeniumdiolates, S-nitrosothiols, and mesoionic oxatriazolederivatives.

[0074] NO release stimulators include, without limitation, adenosine.

[0075] Anti-sclerosing agents include, without limitation, collagenasesand halofuginone.

[0076] Vasoactive agents include, without limitation, nitric oxide,adenosine, nitroglycerine, sodium nitroprusside, hydralazine,phentolamine, methoxamine, metaraminol, ephedrine, trapadil,dipyridamole, vasoactive intestinal polypeptides (VIP), arginine, andvasopressin.

[0077] Endothelial growth factors include, without limitation, VEGF(Vascular Endothelial Growth Factor) including VEGF-121 and VEG-165, FGF(Fibroblast Growth Factor) including FGF-1 and FGF-2, HGF (HepatocyteGrowth Factor), and Ang1 (Angiopoietin 1).

[0078] Beta blockers include, without limitation, propranolol, nadolol,timolol, pindolol, labetalol, metoprolol, atenolol, esmolol, andacebutolol.

[0079] Hormones include, without limitation, progestin, insulin, theestrogens and estradiols (e.g., estradiol, estradiol valerate, estradiolcypionate, ethinyl estradiol, mestranol, quinestrol, estrond, estronesulfate, and equilin).

[0080] Statins include, without limitation, mevastatin, lovastatin,simvastatin, pravastatin, atorvastatin, and fluvastatin.

[0081] Insulin growth factors include, without limitation, IGF-1 andIGF-2.

[0082] Antioxidants include, without limitation, vitamin A, carotenoidsand vitamin E.

[0083] Membrane stabilizing agents include, without limitation, certainbeta blockers such as propranolol, acebutolol, labetalol, oxprenolol,pindolol and alprenololi.

[0084] Calcium antagonists include, without limitation, amlodipine,bepridil, diltiazem, felodipine, isradipine, nicardipine, nifedipine,nimodipine and verapamil.

[0085] Retinoids include, without limitation, all-trans-retinol,all-trans-14-hydroxyretroretinol, all-trans-retinaldehyde,all-trans-retinoic acid, all-trans-3,4-didehydroretinoic acid,9-cis-retinoic acid, 11-cis-retinal, 13-cis-retinal, and 13-cis-retinoicacid.

[0086] Anti-macrophage substances include, without limitation, NOdonors.

[0087] Anti-leukocytes include, without limitation, 2-CdA, IL-1inhibitors, anti-CD 116/CD 18 monoclonal antibodies, monoclonalantibodies to VCAM, monoclonal antibodies to ICAM, and zincprotoporphyrin.

[0088] Cyclooxygenase inhibitors include, without limitation, Cox-1inhibitors and Cox-2 inhibitors (e.g., CELEBREX® and VIOXX®).

[0089] immunomodulatory agents include, without limitation,immunosuppressants (see above) and immunostimulants (e.g., levamisole,isoprinosine, Interferon alpha, and Interleukin-2).

[0090] ACE inhibitors include, without limitation, benazepril,captopril, enalapril, fosinopril sodium, lisinopril, quinapril,ramipril, and spirapril.

[0091] Cell sensitizers to insulin include, without limitation,glitazones, P par agonists and metformin.

[0092] Antisense oligonucleotides include, without limitation,resten-NG.

[0093] Cardio protectants include, without limitation, VIP, pituitaryadenylate cyclase-activating peptide (PACAP), apoA-I milano, amlodipine,nicorandil, cilostaxone, and thienopyridine.

[0094] Petidose inhibitors include, without limitation, omnipatrilat.

[0095] Anti-restenotics include, without limitation, includevincristine, vinblastine, actinomycin, epothilone, paclitaxel, andpaclitaxel derivatives (e.g., docetaxel).

[0096] Miscellaneous compounds include, without limitation, Adiponectin.

[0097] While the invention has been described in detail with referenceto the preferred embodiments thereof, it will be apparent to one skilledin the art that various changes and modifications can be made andequivalents employed, without departing from the present invention.

What is claimed is:
 1. An implantable medical device comprising: adevice body including a beneficial agent arranged for delivery from thedevice body to an implantation site within a patient, the beneficialagent configured to be selectively modulated after implantation withinthe patient by an activating/deactivating means, wherein the beneficialagent at a first region of the device body can be modulated by theactivating/deactivating means to create a different agent deliveryprofile than the beneficial agent at a second region of the device body.2. The device of claim 1, wherein the beneficial agent is configured tobe modulated after implantation within the patient by theactivating/deactivating means in the form of an energy emittingcatheter.
 3. The device of claim 1, wherein the beneficial agent isconfigured to be modulated after implantation within the patient by theactivating/deactivating means in the form of a chemical agent.
 4. Thedevice of claim 1, wherein the beneficial agent is substantiallyuniformly distributed in the device body.
 5. The device of claim 1,comprising a barrier layer configured to be acted on by theactivating/deactivating means to release or retain the beneficial agentin the first or second regions.
 6. The device of claim 1, whereinbeneficial agent is contained in a matrix or binder configured to beacted on by the activating/deactivating means to release or retain thebeneficial agent in the first or second regions.
 7. The device of claim1, wherein the device body is a cylindrical, expandable medical device.8. The device of claim 7, wherein the device is a stent.
 9. The deviceof claim 7, wherein the beneficial agent is contained in a plurality ofrecesses in the medical device.
 10. The device of claim 7, wherein thebeneficial agent is containing in a plurality of through holes in themedical device.
 11. The device of claim 1, wherein the beneficial agentis selected to treat vascular disease.
 12. The device of claim 1,wherein the beneficial agent is located in a plurality of openings inthe device body.
 13. A beneficial agent delivery system comprising: animplantable medical device including a beneficial agent arranged fordelivery to an implantation site within a patient, the beneficial agentconfigured to be modulated after implantation within the patient by anactivating/deactivating means; and a selective modulation catheterhaving an activating/deactivating means configured to activate ordeactivate the beneficial agent on a first region of the medical deviceto create a different delivery profile than the beneficial agent on asecond region of the medical device.
 14. The beneficial agent deliverysystem of claim 13, wherein the modulation catheter deactivates thebeneficial agent on the first region of the medical device by increasingthe delivery period.
 15. The beneficial agent delivery system of claim13, wherein the modulation catheter deactivates the beneficial agent onthe first region of the medical device by blocking beneficial agentdelivery.
 16. The beneficial agent delivery system of claim 13, whereinthe modulation catheter deactivates the beneficial agent on a firstregion of the medical device by deactivating the agent.
 17. Thebeneficial agent delivery system of claim 13, wherein the modulationcatheter activates the beneficial agent on a first region of the medicaldevice by modulating the delivery period.
 18. The beneficial agentdelivery system of claim 13, wherein the modulation catheter activatesthe beneficial agent on a first region of the medical device byreleasing the beneficial agent.
 19. The beneficial agent delivery systemof claim 13, wherein the selective modulation catheter includes anenergy emitter which acts on the beneficial agent or the implantablemedical device.
 20. The beneficial agent delivery system of claim 19,wherein the energy emitter emits light, ultrasonic energy, or radiation.21. The beneficial agent delivery system of claim 13, wherein theselective modulation catheter includes means for delivering a chemicalagent which acts on the beneficial agent or the implantable medicaldevice.
 22. The beneficial agent delivery system of claim 13, whereinthe implantable medical device is a stent.
 23. The beneficial agentdelivery system of claim 13, wherein the beneficial agent is located ina plurality of openings in the implantable medical device.
 24. A methodof beneficial agent delivery with selective modulation of beneficialagent delivery, the method comprising: implanting an implantable medicaldevice including a beneficial agent within a patient; delivering anactivation/deactivation means to a location of the implanted medicaldevice; and modulating the amount of drug delivered from a first regionof the implanted medical device with the activation/deactivation meanswithout modulating the amount of beneficial agent delivered from asecond region of the implanted medical device.
 25. The method of claim24, wherein the beneficial agent is selected to treat vascular disease.26. The method of claim 24, wherein step of modulating is performed byselectively delivering energy to the first region of the implantedmedical device.
 27. The method of claim 24, wherein the step ofmodulating is performed by selectively delivering a chemical to thefirst region of the implanted medical device.
 28. The method of claim24, wherein the step of delivering an activation/deactivation meansincludes delivering a catheter containing the activation/deactivationmeans to the location of the implanted medical device.
 29. The method ofclaim 24, wherein the implantable medical device is a stent.
 30. Anbeneficial agent delivery system comprising: an expandable implantablestent; a beneficial agent affixed to the stent, the beneficial agenthaving an initial agent release profile; an activating/deactivatingmeans, wherein the beneficial agent release profile can be modulated bythe activating/deactivating means after implantation of the stent withina patient to create an agent release profile different from the initialagent release profile.
 31. The system of claim 30, wherein thebeneficial agent is configured to be modulated after implantation withinthe patient by the activating/deactivating means in the form of anenergy emitting catheter.
 32. The system of claim 30, wherein thebeneficial agent is configured to be modulated after implantation withinthe patient by the activating/deactivating means in the form of achemical agent.
 33. The system of claim 30, wherein the beneficial agentis substantially uniformly distributed in the device body.
 34. Thesystem of claim 30, comprising a barrier layer configured to be acted onby the activating/deactivating means to create the different agentrelease profile.
 35. The system of claim 30, wherein beneficial agent iscontained in a matrix or binder configured to be acted on by theactivating/deactivating means to release or retain the beneficial agentin the first or second regions.
 36. The system of claim 30, wherein thebeneficial agent is contained in a plurality of recesses in the stent.37. The system of claim 30, wherein the beneficial agent is containingin a plurality of through holes in the stent.
 38. The system of claim30, wherein the beneficial agent is selected to treat vascular disease.39. The system of claim 30, wherein the beneficial agent is configuredfor substantially no release until modulation by theactivating/deactivating means.
 40. The system of claim 30, furthercomprising an additional beneficial agent affixed to the stent andconfigured to be released without activation.
 41. A method of beneficialagent delivery from a stent, the method comprising: implanting a stentincluding a first beneficial agent and a second beneficial agent withina lumen; delivering the first beneficial agent from the stent;determining whether the second beneficial agent is to be delivered;delivering an activation means to the stent; and modulating the amountof second beneficial agent delivered from the stent with the activationmeans.
 42. The method of claim 41, wherein the delivery of theactivation/deactivation means does not substantially modulating theamount of the first beneficial agent delivered from the stent.
 43. Themethod of claim 41, wherein the step of modulating is performed bydelivering energy to the stent.
 44. The method of claim 41, wherein thestep of modulating is performed by delivering a chemical to the stent.45. A method of beneficial agent delivery from a stent, the methodcomprising: implanting a stent including a first beneficial agent;delivering the first beneficial agent from the stent; determining whendelivery of the first beneficial agent is to be terminated; delivering adeactivation means to the stent; and substantially terminating theamount of second beneficial agent delivered from the stent with thedeactivation means.
 46. The method of claim 45, wherein the step ofterminating is performed by delivering energy to the stent.
 47. Themethod of claim 45, wherein the step of terminating is performed bydelivering a chemical to the stent.